Melanoma provides a unique model for studies of gene-gene and gene-environmental interaction in the development of cancer. It has several key features. First, there is a major environmental cause of melanoma, exposure to solar UV radiation, which may account for as much as 90 percent of cases in populations of European origin. Second, variants of or mutations in at least three classes of genes with very different functions may determine variation in melanoma risk-cell cycle genes, nucleotide excision repair genes and genes relating to cutaneous pigmentation. Third, the latter two classes of genes are involved in protection against the effects of UV radiation. These features permit the study of gene-gene and gene-environment interactions under circumstances largely free from confounding environmental factors and with genes whose functions and relationships to the environmental factor are reasonably well understood. We hypothesize that there are wide variations among individuals in terms of susceptibility to melanoma. This variation is probably influenced in a heterogeneous manner by multiple susceptibility genes, and sun exposure, the major known exogenous factor, may exert its influence interacting with these genes. Our proposed study will permit evaluation of the public health impact of genetic mutations and polymorphisms and their interaction with sun exposure, via estimation of relevant population parameters in a novel study design. In a large, international population-based case control study covering a wide range of latitudes, we will 1. Determine the relative risk for developing melanoma due to germline mutations and polymorphisms in the cell cycle genes, CDKN2A and CDK4. 2. Determine the relative risk for developing melanoma due to polymorphisms in the melanocortin receptor gene MC1R, a major pigmentary gene. 3. Determine the relative risk for developing melanoma due to allelic variation in the DNA repair genes that specialize in removing DNA damage due to UV radiation, the nucleotide excision repair genes (NER). 4. Analyze the interactions among genetic variants that are associated with the development of melanoma and their association with solar UV radiation. We will do this by way of a novel epidemiological design, a population-based case-control study in which the controls are subjects with incident primary melanoma and the cases are subjects diagnosed with a second or higher order primary melanoma. This design offers substantially greater statistical power to test our hypotheses than a classical case-control study with general population non-diseased control (Begg and Berwick 1997) and, in principle, higher participation rates by both cases and controls. It has substantial potential for application to other areas of cancer susceptibility.